Background: The posterior communicating artery (PComA) is among the most common intracranial aneurysm locations, but flow diverter (FD) treatment with the widely used pipeline embolization device (PED) remains an off-label treatment that is not well understood. PComA aneurysm flow diversion is complicated by the presence of fetal posterior circulation (FPC), which has an estimated prevalence of 4-29% and is more common in people of black (11.5%) than white (4.
View Article and Find Full Text PDFInt J Numer Method Biomed Eng
October 2024
Reduced order modelling (ROMs) methods, such as proper orthogonal decomposition (POD), systematically reduce the dimensionality of high-fidelity computational models and potentially achieve large gains in execution speed. Machine learning (ML) using neural networks has been used to overcome limitations of traditional ROM techniques when applied to nonlinear problems, which has led to the recent development of reduced order models augmented by machine learning (ML-ROMs). However, the performance of ML-ROMs is yet to be widely evaluated in realistic applications and questions remain regarding the optimal design of ML-ROMs.
View Article and Find Full Text PDFVascular flow modelling can improve our understanding of vascular pathologies and aid in developing safe and effective medical devices. Vascular flow models typically involve solving the nonlinear Navier-Stokes equations in complex anatomies and using physiological boundary conditions, often presenting a multi-physics and multi-scale computational problem to be solved. This leads to highly complex and expensive models that require excessive computational time.
View Article and Find Full Text PDFAldehyde oxidase (AOX) is a cytosolic drug-metabolizing enzyme which has attracted increasing attention in drug development due to its high hepatic expression, broad substrate profile and species differences. In contrast, there is limited information on the presence and activity of AOX in extrahepatic tissues including ocular tissues. Because several ocular drugs are potential substrates for AOX, we performed a comprehensive analysis of the AOX1 expression and activity profile in seven ocular tissues from humans, rabbits, and pigs.
View Article and Find Full Text PDFHow prevalent is spontaneous thrombosis in a population containing all sizes of intracranial aneurysms? How can we calibrate computational models of thrombosis based on published data? How does spontaneous thrombosis differ in normo- and hypertensive subjects? We address the first question through a thorough analysis of published datasets that provide spontaneous thrombosis rates across different aneurysm characteristics. This analysis provides data for a subgroup of the general population of aneurysms, namely, those of large and giant size (>10 mm). Based on these observed spontaneous thrombosis rates, our computational modeling platform enables the first observational study of spontaneous thrombosis prevalence across a broader set of aneurysm phenotypes.
View Article and Find Full Text PDFDespite success on multi-contrast MR image synthesis, generating specific modalities remains challenging. Those include Magnetic Resonance Angiography (MRA) that highlights details of vascular anatomy using specialised imaging sequences for emphasising inflow effect. This work proposes an end-to-end generative adversarial network that can synthesise anatomically plausible, high-resolution 3D MRA images using commonly acquired multi-contrast MR images (e.
View Article and Find Full Text PDFPeptide therapeutics showcase number of advantages compared to the traditional small molecule drugs, e,g. they usually have higher affinity to target and lower toxicity profiles. Endogenous peptides are mostly cleared from the body through renal clearance or proteolytic hydrolysis.
View Article and Find Full Text PDFAs a multitissue organ, the eye possesses unique anatomy and physiology, including differential expression of drug-metabolizing enzymes. Several hydrolytic enzymes that play a major role in drug metabolism and bioactivation of prodrugs have been detected in ocular tissues, but data on their quantitative expression is scarce. Also, many ophthalmic drugs are prone to hydrolysis.
View Article and Find Full Text PDFThe cost of clinical trials is ever-increasing. In-silico trials rely on virtual populations and interventions simulated using patient-specific models and may offer a solution to lower these costs. We present the flow diverter performance assessment (FD-PASS) in-silico trial, which models the treatment of intracranial aneurysms in 164 virtual patients with 82 distinct anatomies with a flow-diverting stent, using computational fluid dynamics to quantify post-treatment flow reduction.
View Article and Find Full Text PDFHydrolytic reactions constitute an important pathway of drug metabolism and a significant route of prodrug activation. Many ophthalmic drugs and prodrugs contain ester groups that greatly enhance their permeation across several hydrophobic barriers in the eye before the drugs are either metabolized or released, respectively, hydrolysis. Thus, the development of ophthalmic drug therapy requires the thorough profiling of substrate specificities, activities, and expression levels of ocular esterases.
View Article and Find Full Text PDFInt J Numer Method Biomed Eng
January 2020
Computational fluid dynamics models are increasingly proposed for assisting the diagnosis and management of vascular diseases. Ideally, patient-specific flow measurements are used to impose flow boundary conditions. When patient-specific flow measurements are unavailable, mean values of flow measurements across small cohorts are used as normative values.
View Article and Find Full Text PDFTreatment of intracranial aneurysms with flow-diverting stents is a safe and minimally invasive technique. The goal is stable embolisation that facilitates stent endothelialisation, and elimination of the aneurysm. However, it is not fully understood why some aneurysms fail to develop a stable clot even with sufficient levels of flow reduction.
View Article and Find Full Text PDFCalcipotriol (MC903) is a side chain analogue of the biologically active 1,25-dihydroxyvitamin D [1,25(OH)D]. Due to its anti-inflammatory and anti-proliferative effects on stromal cells, calcipotriol is a promising candidate for the local treatment of arthritis. In this preliminary work, we studied the pharmacokinetics and safety of calcipotriol after an IV (0.
View Article and Find Full Text PDFThere is emerging evidence suggesting that Alzheimer's disease is a vascular disorder, caused by impaired cerebral perfusion, which may be promoted by cardiovascular risk factors that are strongly influenced by lifestyle. In order to develop an understanding of the exact nature of such a hypothesis, a biomechanical understanding of the influence of lifestyle factors is pursued. An extended poroelastic model of perfused parenchymal tissue coupled with separate workflows concerning subject-specific meshes, permeability tensor maps and cerebral blood flow variability is used.
View Article and Find Full Text PDFObjective: Alzheimer's disease (AD) is a progressive and debilitating neurodegenerative disease; a major health concern in the ageing population with an estimated prevalence of 46 million dementia cases worldwide. Early diagnosis is therefore crucial so mitigating treatments can be initiated at an early stage. Cerebral hypoperfusion has been linked with blood-brain barrier dysfunction in the early stages of AD, and screening for chronic cerebral hypoperfusion in individuals has been proposed for improving the early diagnosis of AD.
View Article and Find Full Text PDFAdverse wall shear stress (WSS) patterns are known to play a key role in the localisation, formation, and progression of intracranial aneurysms (IAs). Complex region-specific and time-varying aneurysmal WSS patterns depend both on vascular morphology as well as on variable systemic flow conditions. Computational fluid dynamics (CFD) has been proposed for characterising WSS patterns in IAs; however, CFD simulations often rely on deterministic boundary conditions that are not representative of the actual variations in blood flow.
View Article and Find Full Text PDFWiley Interdiscip Rev Syst Biol Med
July 2017
Virtual endovascular treatment models (VETMs) have been developed with the view to aid interventional neuroradiologists and neurosurgeons to pre-operatively analyze the comparative efficacy and safety of endovascular treatments for intracranial aneurysms. Based on the current state of VETMs in aneurysm rupture risk stratification and in patient-specific prediction of treatment outcomes, we argue there is a need to go beyond personalized biomechanical flow modeling assuming deterministic parameters and error-free measurements. The mechanobiological effects associated with blood clot formation are important factors in therapeutic decision making and models of post-treatment intra-aneurysmal biology and biochemistry should be linked to the purely hemodynamic models to improve the predictive power of current VETMs.
View Article and Find Full Text PDFRationale: Menthofuran is a hepatotoxin and a major metabolite of pulegone, a monoterpene found in the essential oils of many mint species. It is bioactivated by cytochrome P450 (CYP) enzymes to reactive metabolites, which may further react with glutathione to form S-linked and N-linked conjugates. The tandem mass spectrometric (MS/MS) fragmentation pathways of rarely observed N-linked conjugates, and the differences to fragmentation of S-linked conjugates, have not been reported in the literature previously, although this information is essential to enable comprehensive MS/MS-based screening methods covering the both types of conjugates.
View Article and Find Full Text PDFFalse tendons (FTs) are fibrous or fibromuscular bands that can be found in both the normal and abnormal human heart in various anatomical forms depending on their attachment points, tissue types, and geometrical properties. While FTs are widely considered to affect the function of the heart, their specific roles remain largely unclear and unexplored. In this paper, we present an in silico study of the ventricular activation time of the human heart in the presence of FTs.
View Article and Find Full Text PDFMany carboxylic acid-containing drugs are associated with idiosyncratic drug toxicity (IDT), which may be caused by reactive acyl glucuronide metabolites. The rate of acyl migration has been earlier suggested as a predictor of acyl glucuronide reactivity. Additionally, acyl Coenzyme A (CoA) conjugates are known to be reactive.
View Article and Find Full Text PDFThe objective was to compare several in vitro human liver-derived subcellular and cellular incubation systems for the formation of GSH-trapped reactive metabolites. Incubations of pooled human liver microsomes, human liver S9 fractions, HepaRG-cells, and human hepatocytes were performed with glutathione as a trapping agent. Experiments with liver S9 were performed under two conditions, using only NADPH and using a full set of cofactors enabling also conjugative metabolism.
View Article and Find Full Text PDFRapid Commun Mass Spectrom
March 2015
Rationale: Metalloporphyrins can be useful in the production of drug metabolites, as they enable easier production of oxidative metabolites usually produced by the cytochrome P450 enzymes. Our aim was to test metalloporphyrin-based biomimetic oxidation (BMO) methods for production and S-glutathione trapping of reactive drug metabolites in addition to phase I metabolites.
Methods: Clozapine, ticlopidine and citalopram were selected as model compounds.
Int J Numer Method Biomed Eng
July 2013
The solution of inverse problems in cardiovascular mathematics is computationally expensive. In this paper, we apply a domain parametrization technique to reduce both the geometrical and computational complexities of the forward problem and replace the finite element solution of the incompressible Navier-Stokes equations by a computationally less-expensive reduced-basis approximation. This greatly reduces the cost of simulating the forward problem.
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